Preparation of selegiline

ABSTRACT

A process for preparing selegiline hydrochloride by reaction of R-(-)-N,α-dimethylphenylethylamine with 3-bromo-1-propyne is described, which consists in reacting the substances in a molar ratio of approximately 2:1 at 30°-50° C. in a solvent mixture of an aromatic hydrocarbon and water and isolating the selegiline from the organic phase and converting it into the hydrochloride.

This application is a 571 of PCT/EP95/03460 filed Feb. 9, 1995.

The present invention relates to a novel process for preparingselegiline.

Selegiline is the (R)-(-)-isomer of deprenyl(═N,α-dimethyl-N-2-propynylphenethylamine), which has the formula

    C.sub.6 H.sub.5 --CH.sub.2 --CH(CH.sub.3)--N(CH.sub.3)--CH.sub.2 --C═CH I.

A number of preparation processes, which deal both with the preparationof racemic product and the optical isomers for the synthesis of deprenylor its antipodes, are known. The starting material used is racemic oroptically active N,α-dimethylphenethylamine C₆ H₅ --CH₂ --CH(CH₃)--NH--CH₃ (═II)!.

CH Patent 393,306 describes, inter alia, the preparation of racemicdeprenyl starting from II with the aid of a metalating agent such aslithium amide or phenylsodium and subsequent alkylation for ten hours inboiling toluene with 3-bromo-1-propyne. Reactions of this type canhardly be carried out on an industrial scale.

According to another chemical process (NL-OS 6,605,956), II can bereacted with propargylaldehyde and the resulting intermediate can bereduced with aluminum amalgam. The disadvantages of this process are thestrong tendency of the propargylaldehyde to polymerize under thereaction conditions, and for it to cause severe skin irritation. Inaddition, mercury and its salts are severe (environmental pollutants,which can only be disposed of at great cost.

The preparation of deprenyl by reaction of α-methylphenylethyl chlorideby means of N-methylpropynylamine in a closed tube at 80° C. describedin DE-AS 1,227,447 cannot be realized on an industrial scale in practicebecause of the poor yield and the high costs of theN-methylpropynylamine. The high costs of the reagents employed make theprocess economically inefficient.

According to DE-AS 1,227,447, II is allowed to react with1,3-dibromopropene at 100° C. for 7 hours. Unreacted starting materialis converted by reaction with benzoyl chloride intoN,α-dimethyl-N-benzoylphenethylamine, which is separated from thedesired final product. Hydrogen bromide has to be eliminated from theresulting N,α-dimethyl-N-3-bromo-2-propenylphenethylamine under theaction of alcoholic/aqueous potassium hydroxide solution in order toobtain the desired propynyl compound. This process is laborious,time-consuming and unsuitable for production on an industrial scale.

Finally, DE-AS 1,227,447 (cf. Example 5) describes the reaction ofpropargyl bromide with twice the molar amount ofN-(1-phenylisopropyl)-methylamino in the absence of a solvent at 100° C.This process does give a relatively good yield, but is not suitable foran industrial-scale synthesis because isolation and purification of theend product are extremely elaborate.

The same goes for the reaction, cited in Acta Pharm. Hung. 1992, 62, 201(page 204), of N-(1-phenylisopropyl)-methylamine with acetylene in thepresence of paraformaldehyde and CuCl₂ (AT 252,901). The selegiline hasto be purified by distillation in this reaction.

An elaborate purification procedure is also necessary for the selegilineproduced in accordance with H. Cabelled Compds. Rodiopharm 1988, 25, 1(page 7).

EP Patent 99,302 describes the alkylation of (R)-II with3-bromo-1-propyne in a two-phase binary system of benzene and aqueousalkali at a starting temperature of 60° C. Working at elevatedtemperature and the use of aqueous sodium hydroxide solution, however,cause problems due to the presence of 3-bromo-1-propyne, eg. ready andincreased formation of polymeric products.

According to a further method (EP-OS 344,675), alkylation with3-bromo-1-propyne is carried out in halogen-containing aliphatichydrocarbons using potassium carbonate. The alkylating agent and theauxiliary base are used in an excess of at least 10%. The total amountof 3-bromo-1-propyne is added in a single portion or in a time intervalof only 5 minutes. The excess and addition of a single portion areunnecessary for the course of the alkylation, since the yields ofselegiline hydrochloride are only barely over 50%. Additionally, the useof halogen-containing hydrocarbons, such as chloroform in particular, isnot safe from the occupational and environmental points of view becauseof the carcinogenicity of the solvent.

These known processes are difficult to transfer to a large industrialscale and do not make possible the preparation of selegilinehydrochloride in good yield.

The present invention relates to a process for preparing selegilinehydrochloride by reaction of R-(-)-N,α-dimethylphenylethylamine with3-bromo-1-propyne, which consists in reacting the substances in a molarratio of approximately 2:1 at 30°-50° C. in a solvent mixture of anaromatic hydrocarbon and water and in the absence of a catalyst, andisolating the selegiline from the organic phase and converting it intothe hydrochloride.

The molar ratio of II to 3-bromo-1-propyne should be such that theamount of II is just adequate to bind the hydrogen bromide formed in thereaction. As a rule, somewhat less than 2 mol of II per mole of3-bromo-1-propyne are needed for this. An excess of II which may bepresent after the end of the reaction should be neutralized, preferablyusing HBr.

The reaction is carried out at 30°-50° C., preferably at 35°-45° C. Thereaction is complete, as a rule, after 5 hours. The reaction time can beshortened by cooling.

The reaction temperature is regulated by the rate of addition of the3-bromopropyne.

The reaction is carried out in a two-phase system of water and anaromatic hydrocarbon such as benzene, toluene, ethylbenzene, o-, m- orp-xylenes or trialkylated benzene, such as mesitylene. Toluene is thebest-suited hydrocarbon.

It is important that the bromide ion formed in the course of thealkylation is rapidly bound by the organic base which is present inexcess and passes into the aqueous phase as rapidly as possible as aneasily soluble salt.

The amount of water in the two-phase system should be over 10%,preferably 20% or more. Amounts of over 30% do not provide any furtheradvantages.

A special feature of the process is that no catalyst is needed.

During the reaction, the selegiline formed passes into the organicphase. After concentrating the organic phase, the residue is taken up ina polar solvent, such as acetone, methyl ethyl ketone or other lowmolecular weight ketones. The solution is filtered, if desired afteraddition of active carbon. The hydrochloride is then precipitated usinghydrogen chloride.

Further selegiline hydrochloride can be isolated from the mother liquor.

The compound II can be extracted from the aqueous phase after additionof alkali. The compound II can also be used for a further reactionmixture.

The novel process has the advantage that it yields selegilinehydrochloride in very good yield and purity. Moreover, the process issimple and can be carried out without relatively great cost. Thus, forexample, relatively high temperatures are not needed.

EXAMPLE

A 500 ml three-necked flask, provided with a reflux condenser, stirrerand dropping funnel, was flushed with nitrogen, 124 g of(R)-(-)-N,α-dimethylphenylethylamine were introduced and heated to38°-42° C. while stirring with 160 ml of toluene and 40 ml of water, and49.3 g of pure 3-bromo-1-propyne were added dropwise with vigorousstirring in the course of 3 h in such a way that the temperature did notexceed 40°-45° C. After addition was complete, the reaction mixture wasstirred at 40°-45° C. for a further 5 h to complete the reaction andallowed to cool to room temperature, whereupon 2 phases were formed.After separation of the two phases, the content of unreacted(R)-(-)-N,α-dimethylphenylethylamine in the organic phase wasdetermined, the equivalent amount of hydrobromic acid was added, and themixture was stirred vigorously for 15 min and then allowed to stand for15 min. The toluene phase was separated from the aqueous phase andwashed twice with 50 ml of water each time. The combined aqueousextracts were collected. The toluene phase was freed completely fromwater and toluene at 50° C. in vacuo. The residue was dissolved in 300ml of acetone, treated with 1 g of activated carbon with stirring andfiltered in vacuo. 15.1 g of hydrogen chloride gas were passed into theacetone solution at ≦30° C. while stirring and cooling. A pH of about 2was established. The reaction mixture was cooled to 20° C. whilestirring and stirring was continued for 6 h. The precipitated crystalswere filtered off with suction under reduced pressure, washed with 30 mlof acetone and dried at 70° C. in vacuo. 81.7 g of selegilinehydrochloride were obtained, m.p. 142°-145° C.;

α!_(D) ²⁰ =11.8°/c=10, water (yield 88%).

About 80% of the solvent were distilled off at normal pressure from theacetone mother liquor of the first crystallizate. After cooling themother liquor to 20° C. and crystallizing for several hours, a secondcrystallizate was obtained which was filtered off with suction underreduced pressure, washed with a little acetone and dried in vacuo at 70°C. A further 8 g of selegiline hydrochloride were obtained, which wasrecrystallized from aqueous acetone with addition of activated carbon.4.6 g of selegiline hydrochloride were obtained, m.p. 142°-147° C.;

α!_(D) ²⁰ =12° c=10, water (yield 5%).

The combined aqueous solutions were treated with sodium hydroxidesolution. The (R)-(-)-N,α-dimethylphenylethylamine was extracted withtoluene. The base recovered in this way can be used again for the nextbatch for the preparation of selegiline hydrochloride.

We claim:
 1. A process for preparing selegiline hydrochloride byreaction of R-(-)-N,α-dimethylphenylethylamine with 3-bromo-1-propyne,which comprises reacting the substances in a molar ratio ofapproximately 2:1 at 30°-50° C. in a solvent mixture of an aromatichydrocarbon and water in the absence of a catalyst, and isolating theselegiline from the organic phase and converting it into thehydrochloride.
 2. The process of claim 1, wherein the reaction iscarried out at a temperature of from 35° to 45° C.
 3. The process ofclaim 1, wherein the reaction is carried out at a temperature of from40° to 45° C.